Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment

RB激活对胰腺癌表观基因组和肿瘤微环境的影响

• 批准号: 10673462
• 负责人: Erik Knudsen
• 金额: $ 50.52万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673462
• 关键词: Antigen Presentation; Automobile Driving; Biochemical; CDK4 gene; Cancer Etiology; Cell Cycle; Cell division; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Complement; Complex; Correlative Study; Coupled; Cytostatics; Data; Disease; Effectiveness; Elements; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Growth; Immune response; Immune system; Immunocompetent; Immunologics; Immunotherapy; Interferons; Intervention; KRAS2 gene; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Population; Pre-Clinical Model; Prognosis; Proliferating; Publishing; Regulation; Regulatory Element; Resistance; Specimen; Survival Rate; Therapeutic; Tissues; Tumor Biology; United States; Work; epigenome; immunoengineering; improved outcome; inhibitor; neoplastic cell; novel strategies; pancreatic ductal adenocarcinoma model; programs; response; retinoblastoma tumor suppressor; targeted treatment; therapy development; therapy resistant; treatment response; tumor; tumor microenvironment; tumorigenesis; tumorigenic

Pancreatic ductal adenocarcinoma (PDAC) represents a therapy recalcitrant disease with 5-year survival rate of approximately 10%. Multiple failed clinical trials reinforce the need for new approaches to treatment that employ rationally developed therapies targeting key genetic features of PDAC tumors as well as the tumor microenvironment. Fundamentally PDAC is a KRAS-driven tumor; however, approaches to target KRAS either genetically or pharmaceutically have led to the realization that tumors can evolve mechanisms to continue cell division in the presence of such interventions. Using a combination of unbiased analyses and patient derived models we find that most tumors have evolved mechanisms to deregulate the retinoblastoma tumors suppressor (RB) pathway that limits the effectiveness of targeting RAS or effector pathways (e.g. MEK inhibition). Consequently, the activation of RB is sufficient to limit the proliferation and tumorigenic growth of PDAC models. In addition to effects on the proliferation, we have found that RB activation is sufficient to coordinate changes in gene expression that impact on genes related to classical vs. basal subtypes of PDAC and immunological gene expression programs (e.g. antigen presentation and interferon response). Unlike cell cycle responses, these changes in gene expression are more heterogeneous and the underlying mechanisms and key regulatory elements remain poorly understood. In Aim 1 we will delineate the RB regulation and mechanisms of gene expression regulation in PDAC models. While RB status clearly has effects on tumor cell division, an important element of RB-pathway activation are effects related to the tumor microenvironment. Preliminary and published data indicate that RB activation has broad effects on the tumor stroma and immunological milieu. Much of these studies have employed systemic strategies that impact on both the tumor and the host. In preliminary data, we have found that activation of RB selectively within the tumor is sufficient to change the fibroblastic and immunological cell subtypes with the tumor, albeit not at the same level of systemic treatments. Here we will interrogate the intersection between the tumor and the microenvironment and how these impact tumor-static response and can be exploited by immunotherapy approaches. Together, Aim 2 will define the impact of RB- activation on the tumor microenvironment using a combination of immune competent models and clinical specimens.

胰腺导管腺癌 (PDAC) 是一种难治性疾病，其 5 年生存率为 大约10%。多项失败的临床试验强化了对新治疗方法的需求 针对 PDAC 肿瘤的关键遗传特征以及肿瘤的合理开发的疗法 微环境。从根本上讲，PDAC 是一种 KRAS 驱动的肿瘤；然而，针对 KRAS 的方法要么 遗传学或药物学使人们认识到肿瘤可以进化出继续细胞生长的机制 在存在此类干预的情况下进行分裂。结合使用无偏见分析和患者衍生数据 我们发现大多数肿瘤已经进化出解除视网膜母细胞瘤肿瘤抑制因子调节的机制 (RB) 途径限制了靶向 RAS 或效应途径的有效性（例如 MEK 抑制）。 因此，RB 的激活足以限制 PDAC 模型的增殖和致瘤生长。 除了对增殖的影响外，我们发现 RB 激活足以协调 影响 PDAC 经典亚型与基础亚型相关基因和免疫基因的基因表达 表达程序（例如抗原呈递和干扰素反应）。与细胞周期反应不同，这些 基因表达的变化更加异质，其潜在机制和关键调控 元素仍然知之甚少。在目标 1 中，我们将描述基因的 RB 调控和机制 PDAC 模型中的表达调控。虽然 RB 状态明显对肿瘤细胞分裂有影响，但一个重要的 RB通路激活的要素是与肿瘤微环境相关的效应。初步并发表 数据表明 RB 激活对肿瘤基质和免疫环境具有广泛的影响。其中很多 研究采用了对肿瘤和宿主都有影响的系统策略。在初步数据中，我们 发现在肿瘤内选择性激活 RB 足以改变成纤维细胞和 免疫细胞亚型与肿瘤的差异，尽管系统治疗的水平不同。在这里我们将 探究肿瘤和微环境之间的交叉点以及它们如何影响肿瘤静态 反应并可以通过免疫治疗方法加以利用。目标 2 将共同定义 RB- 的影响 使用免疫活性模型和临床相结合来激活肿瘤微环境 标本。